Hypertrophic cardiomyopathy is the most common inherited cardiac disease. In about a third to half of kindreds with hypertrophic cardiomyopathy, the disease is linked to the beta myosin heavy chain gene located on chromosome 14. We have described several mutations in the beta myosin heavy chain gene resulting in each case in substitution of one amino acid by another. We have also found that although the disease affects the heart predominantly, the cardiac protein is also expressed in skeletal tissue and that the mutant RNA and protein are also to be found in skeletal muscle. This has led us to perform light microscopic and electron-microscopic examinations of skeletal muscle (soleus muscle of the leg) biopsies from patients with these mutations. Light microscopy revealed the presence of central core disease, a rare autosomal dominant non-progressive myopathy with predominance of type I "slow" fibers and absence of mitochondria from the center of some of the type I fibers. Central core disease and myopathy were present in most patients with distinct mutations in the beta myosin heavy chain gene but not in skeletal biopsies from 5 control subjects nor in 3 patients with hypertrophic cardiomyopathy in whom the disease was not linked to the beta myosin heavy chain gene locus. Thus, the beta myosin associated hypertrophic cardiomyopathy is a disease of skeletal as well as cardiac muscle and some hypertrophic cardiomyopathy patients with distinct beta myosin heavy chain gene mutations have central core disease.